Multiple sclerosis (MS) is a devastating inflammatory and neurodegenerative disorder of the central nervous system (CNS). Currently, there are no effective treatments for Primary Progressive forms of MS (PP-MS) and more than half of Relapsing Remitting forms of MS (RR-MS) fail to respond to existing therapies generating a critically unmet medical need. The ultimate goal of this study is to develop a novel therapeutic drug for MS that interferes with the major inflammatory pathways and provides neuroprotection. Our phase I study established proof-of-principle with Cognosci's innovative anti- inflammatory/neuroprotective ApoE-mimetic peptides that significantly ameliorated disease severity, promoted functional recovery, decreased histopathological signs of disease, and reduced the relapse rate in two experimental autoimmune encephalomyelitis (EAE) models of MS, even when administered after the onset of disease. We EXCEEDED our aims by identifying a new, more potent analog, COG112, which resulted in nearly 100% remission rate in EAE. This Phase II proposal will capitalize on the success of our previous work to examine the mechanism and relative efficacy of three more potent and more drug-like COG compounds in established models of MS. In specific aims 1 and 2, we will identify the optimal candidate from the three COG compounds in myelin oligodendrocyte glycoprotein (MOG)- and proteolipid protein (PLP)-induced EAE models mimicking the PP-MS and RR-MS forms of human MS, respectively. In specific aim 3, we will decipher the molecular and pharmacological mechanisms underlying the effectiveness of COG compounds in the following aspects: 1) if COG compounds can shift Th1 response to Th2 in EAE model; 2) how COG compounds affect the function of antigen-presenting cells; and 3) how COG compounds modulate the phosphorylation of MAP kinase JNK, p38 and transcription factor NF-?B. The data generated by this proposal will enable us to select a lead candidate for the treatment of MS. After the project is completed, this lead will be progressed through the safety pharmacology required by the FDA for submission of an IND application. The completion of the project will also deepen our understanding of the disease and confirm that we have identified a novel therapeutic target for MS. Considering the early age of onset, size of the patient population, debilitating nature of this disease, and the startling healthcare costs, the current project to develop a novel therapy for MS has significant personal, social, and economic benefit to MS patients and their families. [unreadable] [unreadable] [unreadable]